Increased intestinal permeability appears to play a role in the pathogenesis of Type 1 diabetes. We hypothesize that the nature of this permeability defect relates to differences in the proteins of the intestinal intercellular junctions. Manipulation of the junctional defect by specific nutrients holds exciting promise in the prevention of Type 1 diabetes. The rationale underlying these hypotheses is that the gastrointestinal tract, in addition to being a digestive-absorptive organ, is also the largest immune organ of the body. Its massive surface provides for interaction between the external environment and the internal provides greatest potential milieu. When normal barrier function is violated, pathologic inflammatory and/or immune responses may occur. [unreadable] [unreadable] The specific aims of this project are to: [unreadable] 1) Compare Type 1 Biobreeding diabetes prone rats (BBdp) and controls to answer whether there are developmental differences in: a) permeability of the small intestine prior to the development of diabetes at 7, 14, 30, 50 and 60 days of age, b) lntestinal epithelial intercellular junctions and proteins using electron microscopy, immunohistochemistry, and biochemical techniques, or c)The intestinal inflammatory response. [unreadable] 2) 2) Determine whether diets composed of hydrolyzed proteins, specialized fatty acids and/or low dose butyrate, given to BBdp rats during infancy, using a novel feeding technique, will affect barrier function, the development of inflammatory responses, and the subsequent development of insulitis and diabetes. At the end of this project, we will have sufficient data to answer whether developmental differences in intestinal permeability and intercellular junctions exist prior to the development of diabetes in a diabetes-prone rat. This information will justify further evaluation of mechanisms as to how intestinal integrity and tight function proteins relate to the pathogenesis of diabetes. It will also provide evidence for the efficacy of promising nutritional strategies that can be translated to future trials in human infants at risk for Type 1 diabetes. [unreadable] [unreadable]